Design, synthesis, radiolabeling, and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential positron emission tomography tracer for the dopamine D(4) receptors.
Design, synthesis, radiolabeling, and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential positron emission tomography tracer for the dopamine D(4) receptors.
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DOI：
10.1021/jm100925m
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发表时间：
2010-10-28
影响因子：
7.3
通讯作者：
Leopoldo M
中科院分区：
文献类型：
--
作者：
Lacivita E;De Giorgio P;Lee IT;Rodeheaver SI;Weiss BA;Fracasso C;Caccia S;Berardi F;Perrone R;Zhang MR;Maeda J;Higuchi M;Suhara T;Schetz JA;Leopoldo M
在这里，我们描述了与N-[2-[4-（4-氯苯基）哌嗪-1-基]乙基]-3-甲氧基苯酰胺(2)相关的D4多巴胺受体配体的设计、合成、理化和药理评价。结合结构特征来增加对目标受体的亲和力，提高对D2和sigma1受体的选择性，使碳-11或氟-18能够标记，并将亲脂性调整到适合脑渗透和低非特异性结合的最佳范围内。化合物7和13对D4受体具有纳米级亲和力，对D2和D3多巴胺受体5-HT1A、5-HT2A和5-HT2C 5-羟色胺受体和sigma1受体具有100倍的选择性，logP = 2.37-2.55。经腹腔给药后，两种化合物均迅速进入中枢神经系统。用碳-11对N-[2-[4-（3-氰吡啶-2-基）哌嗪-1-基]乙基]-3-甲氧基苯甲酰胺(7)的甲氧基进行放射性标记，并在非人灵长类动物中进行PET分析。[11C]7在视网膜区域（一个含有高密度D4受体的组织）的后眼，时间依赖性地积累至饱和。
Here we describe the design, synthesis, physicochemical, and pharmacological evaluation of D4 dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D2 and sigma1 receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D4 receptor, > 100-fold selectivity over D2 and D3 dopamine receptor 5-HT1A, 5-HT2A and 5-HT2C serotonin receptors and sigma1 receptors, and logP = 2.37–2.55. Following intraperitoneal administration, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide (7) was radiolabelled with carbon-11 and subjected to PET analysis in non-human primate. [11C]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D4 receptors.
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影响因子：
3.5
作者：
Cummings, David F.;Canseco, Diana C.;Schetz, John A.
通讯作者：
Schetz, John A.
DOI：
10.1124/jpet.108.141531
发表时间：
2009-01-01
影响因子：
3.5
作者：
Ericksen, Spencer S.;Cummings, David F.;Schetz, John A.
通讯作者：
Schetz, John A.
影响因子：
17.7
作者：
Faraone, SV;Doyle, AE;Biederman, J
通讯作者：
Biederman, J
影响因子：
3.6
作者：
Browman, KE;Curzon, P;Fox, GB
通讯作者：
Fox, GB
影响因子：
11
作者：
Grady, DL;Chi, HC;Moyzis, RK
通讯作者：
Moyzis, RK